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Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice.

ABSTRACT: High-fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer's disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects of high fat/high cholesterol levels on cognition and amyloid pathology. Here we show that in 9-month-old APP23 mice, a high-fat/high-cholesterol (HF) diet provided for 4 months exacerbates the AD phenotype evaluated by behavioral, morphological, and biochemical assays. To examine the therapeutic potential of liver X receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant reduction of memory deficits observed during both acquisition and retention phases of the Morris water maze. Moreover, the effects of T0 on cognition correlate with AD-like morphological and biochemical parameters. We found a significant decrease in amyloid plaque load, insoluble Abeta and soluble Abeta oligomers. In vitro experiments with primary glia demonstrate that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on Abeta degradation by microglia. Microdialysis experiments performed on awake freely moving mice showed that T0 decreased Abeta levels in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Abeta clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has critical effects on AD phenotype progression by attenuating Abeta deposition and facilitating its clearance.

SUBMITTER: Fitz NF

PROVIDER: S-EPMC2883862 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice.

Fitz Nicholas F NF Cronican Andrea A Pham Tam T Fogg Allison A Fauq Abdul H AH Chapman Robert R Lefterov Iliya I Koldamova Radosveta R

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100501 20

High-fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer's disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects of high fat/high cholesterol levels on cognition and amyloid pathology. Here we show that in 9-month-old APP23 mice, a high-fat/high-cholesterol (HF) diet provided for 4 months exacerbates the AD phenotype evaluated by behavioral, morphological, and biochemical assays. To exam ...[more]

PMID: 20484628

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Project description:ObjectiveCelastrol was recently identified as a potential novel treatment for obesity. However, the effect of Celastrol on nonalcoholic fatty liver disease (NAFLD) remains elusive. The aim of this study is to evaluate the role of Celastrol in NAFLD.MethodsFunctional studies were performed using wild-type C57BL/6J (WT) mice and liver specific Sirt1-deficient (LKO) mice. The molecular mechanism was explored in primary mouse liver and primary hepatocytes.ResultsWhen WT mice receiving a high-fat diet (HFD) were treated with Celastrol, reductions in body weight, subcutaneous and visceral fat content, and liver lipid droplet formation were observed, along with reduced hepatic intracellular triglyceride and serum triglyceride, free fatty acid, and ALT concentrations. Furthermore, Celastrol decreased hepatic sterol regulatory element binding protein 1c (Srebp-1c) expression, enhanced the phosphorylation of hepatic AMP-activated protein kinase α (AMPKα), and increased the expression of hepatic serine-threonine liver kinase B1 (LKB1). Additionally, Celastrol treatment improved glucose tolerance and insulin sensitivity in WT mice fed the HFD. Celastrol administration also improved the anti-inflammatory and anti-oxidative status by inhibiting nuclear factor kappa B (NFκB) activity and the mRNA levels of proinflammatory cytokines and increasing mitochondrial DNA copy number and anti-oxidative stress genes expression in WT mice liver, in vivo and in vitro. Moreover, Celastrol induced hepatic Sirt1 expression in WT mice, in vivo and in vitro. These Celastrol-mediated protective effects in WT mice fed a HFD were abolished in LKO mice fed a HFD. It was more interesting that Celastrol aggravated HFD-induced liver damage in LKO mice fed a HFD by inhibiting the phosphorylation of AMPKα and boosting the translocation of NFκB into the nucleus, thereby resulting in the increase of Srebp-1c expression and the mRNA levels of liver proinflammatory cytokines.ConclusionsCelastrol ameliorates NAFLD by decreasing lipid synthesis and improving the anti-oxidative and anti-inflammatory status. And Sirt1 has an important role in Celastrol-ameliorating liver metabolic damage caused by HFD.

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Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice.

Publications

Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice.

Similar Datasets

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